1. Field of the Invention
The present invention relates to a method of using L-arginine or pharmaceutically acceptable salts thereof in the treatment of hypertension and other high vascular resistance disorders. High vascular resistance disorders include primary or secondary vasospasm, angina pectoris, cerebral ischemia and preeclampsia of pregnancy. The present invention is also concerned with a method of preventing or treating bronchial asthma using L-arginine or a pharmaceutically acceptable salt thereof.
2. Description of the Prior Art
The disposition of hypertensive patients to develop vascular disease which leads to increased mortality from stroke and myocardial infarction is a major problem in the western world. The development of hypertension can relate to abnormalities in the production or activities of vasoactive substances. Alteration in the responsiveness to both vasoconstrictors and vasodilators has been well documented in spontaneous hypertensive rats, the most frequently used animal model for the study of human essential hypertension. Thus, an increase in the contractile response of vascular smooth muscle of spontaneous hypertensive rats to vasoconstrictors such as norepinephrine as noted by Lais et al, "Mechanism of Vascular Hyperresponsiveness in the Spontaneously Hypertensive Rat", Cir. Res., 36/37: Suppl. 1, I-216 to I-222 (1975), and a decrease in the relaxant response to vasodilators such as acetylcholine, nitrovasodilators, prostaglandin and other arachidonic acid metabolites as noted by Pinto et al, "Arachidonic Acid-Induced Endothelial-Dependent Relaxations of Canine Coronary Arteries: Contribution of a Cytochrome P-450-Dependent Pathway", J Pharmacol. Exp. Therap., 240, 856-863 (1987) and Luscher et al, "Endothelium-Dependent Responses in Carotid and Renal Arteries of Normotensive and Hypertensive Rats", Hypertension, 11, 573-578 (1988), may contribute overall to the development of high blood pressure.
It has also been demonstrated that cytochrome P-450-arachidonate metabolism is increased in the kidney of young spontaneous hypertensive rats and a selective reduction in the formation of these metabolites via induction of heme degradation with SnCl.sub.2 caused a marked decrease in blood pressure as noted by Sacerdoti et al, "Treatment with Tin Prevents the Development of Hypertension in Spontaneously Hypertensive Rats", Science, 243, 388-390 (1989). Martasek et al, "Heme Arginate Lowers Blood Pressure in Spontaneous Hypertensive Rats", Clin. Res., 37, 553A (1989) also noted that other heme oxygenase inducers such as heme arginate have been demonstrated to be an inducer of heme oxygenase causing reduction of renal P-450 and a decrease in blood pressure in young spontaneous hypertensive rats. The blood pressure lowering effect of heme arginate could be attributed to the heme component. The heme effect may be due to an induction of heme oxygenase, since it is blocked by an inhibitor of heme oxygenase.
The relaxation of vascular smooth muscle in response to many substances is typically endothelium-dependent and mediated by endothelium-derived relaxing factors as noted by Furchgott et al, "The Role of Endothelium in the Responses of Vascular Smooth Muscle to Drugs", Ann. Rev. Pharmacol. Toxicol., 24, 175-197 (1984). One of the endothelium-derived relaxing factors has been recently identified as nitric oxide by Palmer et al, "Vascular Endothelial Cells Synthesize Nitric Oxide from L-arginine", Nature, 333, 664-666 (1988); and Ignarro et al, "Endothelium-Derived Nitric Oxide: Actions and Properties", FASEB J., 3, 31-36 (1989). Nitric oxide elicits vasodilation by increasing the formation of c-GMP following direct interaction with the heme component of soluble guanylate cyclase (Ignarro et al, supra).
An increase in hepatic and renal cytochrome P-450 content and its related drug metabolizing enzyme systems has been demonstrated in spontaneous hypertensive rats as noted by Merrick et al, "Alterations in Hepatic Microsomal Drug Metabolism and Cytochrome P450 Proteins in Spontaneously Hypertensive Rats", Pharmacol., 30, 129-135 (1985) and Sacerdoti et al, "Renal Cytochrome P450-Dependent Metabolism of Arachidonic Acid in Spontaneously Hypertensive Rats", Biochem. Pharmacol., 37, 521-527 (1988). More recently Sacerdoti et al demonstrated that abnormalities of renal function in young spontaneous hypertensive rats may be a functional expression of an alteration in renal cytochrome P-450-dependent metabolism of arachidonic acid. Cytochrome P-450 levels are regulated by the availability of cellular heme which in turn is controlled by the levels of heme oxygenase which is the controlling enzyme in the metabolism of heme to bilirubin. Induction of heme oxygenase by heavy metals such as SnCl.sub.2 results in a depletion of renal cytochrome P-450 as described by Kappas et al, "Control of Heme Metabolism with Synthetic Metalloprophyrins", J. Clin. Invest., 77, 335-339 (1986) and Simionatto et al, "Studies on the Mechanism of Sn-Protoporphyrin Suppression and Hyperbilirubinemia: Inhibition of Heme Oxidation and Bilirubin Production", J. Clin. Invest., 75, 513-521 (1985).
Furthermore, it has recently been demonstrated by Escalante et al, "19(S)Hydroxyeicosatetraenoic Acid is a Potent Stimulatior of Renal Na.sup.+ -K.sup.+ -ATPase", Biochem. Biophys. Res. Commun., 152, 1269-1273 (1988) and Escalante et al, "Vasoactivity of 20-Hydroxyeicosatetraenoic Acid is Dependent on Metabolism by Cyclooxygenase", J. Pharmacol. Exp. Therap., 248, 229-232 (1989) that arachidonic acid metabolites of cytochrome P-450 .omega./.omega.-1 hydroxylases, 19(S)-HETE (hydroxyeicosatetragenoic acid) and 20-HETE is a potent renal Na.sup.+ -K.sup.+ -ATPase stimulator and 20-HETE is a vasoconstrictor.
An acute attack of acute intermittent porphyria, a disease caused by inborn errors of porphyrin metabolism, is a life threatening condition, often characterized by agonizing abdominal pain, paresis and frequently accompanied by hypertension. The exact pathogenesis of hypertension in an acute porphyric attack is not well understood. Currently, hemin in the form of heme arginate is used in Europe in the treatment of acute attacks of acute intermittent porphyria so as to normalize the levels of "free" heme and thereby decrease the induced levels of delta-aminolevulinic acid synthetase, an enzyme under negative feedback control by unbound or "free" heme. Kordac et al, "Changes of Myocardial Functions in Acute Hepatic Porphyrias. Role of Heme Arginate Administration", Ann. Med., 21, 273-276 (1989) disclosed the use of heme arginate in the treatment of acute hepatic porphyria. Heme arginate was administered to those patients because it was speculated that acute hypoxia occurs in a porphyrin crisis due to lack of heme. The arginate was used as a way to solubilize the heme for administration to the patient.
It has long been thought that the source of nitric oxide and other nitroso species in animal tissues is L-arginine. Indeed, recent studies have demonstrated that cultured endothelial cells transform L-arginine to the nitroso species, thus supporting the suggestion that L-arginine is a physiological precursor of endothelium-derived nitric acid. Ignarro et al, supra.
Rees et al, "Role of Endothelium-derived Nitric Oxide in the Regulation of Blood Pressure", Proc. Natl. Acad. Sci. USA, 86, 3375-3378 (1989) used N-monomethyl-L-arginine to investigate the role of nitric oxide in the regulation of blood pressure in the anesthetized rabbit. The authors concluded that N-monomethyl-L-arginine caused a dose-dependent increase in mean arterial blood pressure. It was also determined that the administration of L-arginine abolished the inhibition of N-monomethyl-L-arginine within fifteen minutes. Their findings further suggested that there is a continuous utilization of L-arginine for the enzymatic formation of nitric oxide by resistance arteries and provides the first evidence that nitric oxide formation contributes to the regulation of blood pressure. No studies were undertaken to test whether the administration of L-arginine could affect blood pressure and the authors specifically stated that they did not believe that L-arginine directly affected blood pressure.
All investigations into the action of nitric oxide and L-arginine ended there. There nevertheless remained a long-felt need in the art for a way of treating a variety of vascular diseases including hypertension. In addition, there remains a long-felt need in the art for a way to prevent or treat bronchial asthma which involves the narrowing of large and small airways due to spasm of bronchial smooth muscle.